There are many factors which influence the addictiveness of a drug. The route of administration is a major determinant of the speed of drug entry into the body and to receptors in the central nervous system which produce resultant effects. Clinical studies are in progress which determine the importance of different routes of administration and the relationship of blood concentrations of drug and active metabolites to concomitant drug effects. Studies of heroin, cocaine and marijuana administration by the intravenous, smoked, intranasal (heroin and cocaine) and oral routes are underway or have been performed. Concurrent physiological, behavioral and performance measures were collected along with blood specimens. Blood specimens was analyzed for drug and metabolites by solid phase extraction-gas chromatography/mass spectrometry. The intravenous and smoked routes produced a rapid onset of pharmacologic effects together with an early appearance of drug and metabolites in blood. It was evident that the smoking route enables individuals to obtain similar pharmacologic effects as produced by intravenous administration of drug, but without the trauma of needle use. Physiological measures such as pupil diameter were compared to drug and metabolite blood levels. Evidence of delays in distribution to effector sites were observed following marijuana smoking, but drug effects following heroin and cocaine administration coincided more closely with concurrent blood concentrations. Onset to effects were delayed longer following intranasal administration and became pronounced after oral administration.